Base‐Dependent Stereodivergent Intramolecular Aza‐Michael Reaction: Asymmetric Synthesis of 1,3‐Disubstituted Isoindolines

Abstract

The nucleophilic addition (A(N)) / intramolecular aza-Michael reaction (IMAMR) process on Ellman's tert-butylsulfinyl imines, bearing a Michael acceptor in the ortho position, is studied. This reaction affords 1,3-disubstituted isoindolines with a wide range of substituents in good yields and diastereoselectivities. Interestingly, careful choice of the base for the aza-Michael step allows either the cis or the trans diastereoisomers to be exclusively obtained. This stereodivergent cyclization has enabled the synthesis of C2-symmetric bisacetate-substituted isoindolines. In addition, bisacetate isoindolines bearing two well-differentiated ester moieties are also noteworthy because they may allow for the orthogonal synthesis of β,β'-dipeptides using a single nitrogen atom as a linchpin.

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

“…[52] As shown for substrate 40, a first set of conditions involving treatment with TBAF at room temperature allowed the formation of product 41b in good yield and excellent stereoselectivity. If DBU was used as base, formation of 41a was obtained as …”

“…[52] It has been found that the stereochemical behavior of the cyclization depends on the relative configuration between the α-carbon and the stereogenic sulfur atom. In the case of substrates having the same relative configuration as 42, a stereodivergent process was observed and the choice of appropriate reaction conditions made it possible to access, in good yields and excellent stereoselectivity, the corresponding 2,3-disubstituted isoindolines either as trans isomers (43a -kinetic control) or cis isomers (43b -thermodynamic control).…”

Stereoselectivity of the Honda–Reformatsky Reaction in Reactions with Ethyl Bromodifluoroacetate with α-Oxygenated Sulfinylimines

“…Several models have been proposed to rationalize the induction by the sulfinylimine auxiliary. 20 The cyclic Ellman transition state TS-4 has been suggested for the Reformatsky reaction (Zn, refluxing 42,43 . However, given it predicts Re face attack (for an (S)-configured sulfinylimine), it is not consistent with our findings.…”

“…However, this model correctly explained the facial selectivity of addition with allyl zinc to an aryl sulfinylimine (in THF). 43 In contrast, the Barrow chelation model TS-6, 46 involving chelation…”

“…Both TS-7 and TS-5 (which predict opposing facial selectivity) have been successfully used to explain the outcome of additions of allyl zinc to sulfinylimines, 43,47 which shows that the exact conditions, …”